8-20197417-G-T

Variant names:

• chr8-20197417-G-T
• rs116941637
• NM_001693.4:c.11G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001693.4(ATP6V1B2):​c.11G>T​(p.Arg4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,389,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP6V1B2 NM_001693.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 7 publications found

Genes affected

ATP6V1B2 (HGNC:854): (ATPase H+ transporting V1 subunit B2) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. The protein encoded by this gene is one of two V1 domain B subunit isoforms and is the only B isoform highly expressed in osteoclasts. [provided by RefSeq, Jul 2008]

ATP6V1B2 Gene-Disease associations (from GenCC):

• autosomal dominant deafness - onychodystrophy syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy 93

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• Zimmermann-Laband syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: G2P
• DOORS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zimmermann-Laband syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39976865).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001693.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B2	NM_001693.4	MANE Select	c.11G>T	p.Arg4Leu	missense	Exon 1 of 14	NP_001684.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B2	ENST00000276390.7	TSL:1 MANE Select	c.11G>T	p.Arg4Leu	missense	Exon 1 of 14	ENSP00000276390.2	P21281
	ATP6V1B2	ENST00000891263.1		c.11G>T	p.Arg4Leu	missense	Exon 1 of 15	ENSP00000561322.1
	ATP6V1B2	ENST00000958718.1		c.11G>T	p.Arg4Leu	missense	Exon 1 of 14	ENSP00000628777.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 2 AN: 166914 AF XY: 0.0000108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1389800 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690250

African (AFR) AF: 0.00 AC: 0 AN: 28768

American (AMR) AF: 0.00 AC: 0 AN: 35866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23942

East Asian (EAS) AF: 0.00 AC: 0 AN: 32258

South Asian (SAS) AF: 0.00 AC: 0 AN: 79866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4436

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077676

Other (OTH) AF: 0.00 AC: 0 AN: 56748

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.12	T
Polyphen		0.0040	B
Vest4		0.59
MutPred		0.43		Loss of sheet (P = 0.0025)
MVP		0.92
MPC		0.014
ClinPred		0.59	D
GERP RS		3.9
PromoterAI		0.0056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.25
gMVP		0.75
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs116941637; hg19: chr8-20054928;